Trauma history and psychopathology in war-affected refugee children referred for trauma-related mental health services in the United States.
There is an increasing need to deliver effective mental health services to refugee children and adolescents across the United States; however, the evidence base needed to guide the design and delivery of services is nascent. We investigated the trauma history profiles, psychopathology, and associated behavioral and functional indicators among war-affected refugee children presenting for psychological treatment. From the National Child Traumatic Stress Network's Core Data Set, 60 war-affected refugee children were identified (51.7% males, mean age = 13.1 years, SD = 4.13). Clinical assessments indicated high rates of probable posttraumatic stress disorder (30.4%), generalized anxiety (26.8%), somatization (26.8%), traumatic grief (21.4%), and general behavioral problems (21.4%). Exposure to war or political violence frequently co-occurred with forced displacement; traumatic loss; bereavement or separation; exposure to community violence; and exposure to domestic violence. Academic problems and behavioral difficulties were prevalent (53.6% and 44.6%, respectively); however, criminal activity, alcohol/drug use, and self-harm were rare (all < 5.45%). These findings highlight the complex trauma profiles, comorbid conditions, and functional problems that are important to consider in providing mental health interventions for refugee children and adolescents. Given the difficulties associated with access to mental health services for refugees, both preventive and community-based interventions within family, school, and peer systems hold particular promise.


A single strain of Clostridium butyricum induces intestinal IL-10-producing macrophages to suppress acute experimental colitis in mice.
Imbalance in gut bacterial composition provokes host proinflammatory responses causing diseases such as colitis. Colonization with a mixture of Clostridium species from clusters IV and XIVa was shown to suppress colitis through the induction of IL-10-producing regulatory T (Treg) cells. We demonstrate that a distinct Clostridium strain from cluster I, Clostridium butyricum (CB), prevents acute experimental colitis in mice through induction of IL-10, an anti-inflammatory cytokine. However, while CB treatment had no effect on IL-10 production by T cells, IL-10-producing F4/80(+)CD11b(+)CD11c(int) macrophages accumulated in the inflamed mucosa after CB treatment. CB directly triggered IL-10 production by intestinal macrophages in inflamed mucosa via the TLR2/MyD88 pathway. The colitis-preventing effect of CB was negated in macrophage-specific IL-10-deficient mice, suggesting that induction of IL-10 by intestinal macrophages is crucial for the probiotic action of CB. Collectively, CB promotes IL-10 production by intestinal macrophages in inflamed mucosa, thereby preventing experimental colitis in mice.


Foramen magnum metastatic malignant melanoma.
The foramen magnum as a site for brain metastasis is extremely rare. We report the case of a 24-year-old male who presented with features of increased intracranial pressure and lower cranial nerve palsies. Imaging revealed a foramen magnum tumor with extension up to the cerebellar vermis superiorly and into the spinal canal inferiorly (craniospinal mass) with mild obstructive hydrocephalus. A malignant melanoma was completely excised. The patient continued to be tumor-free 24 months later.


The effects of slow-paced versus mechanically assisted breathing on autonomic function in fibromyalgia patients.
Paced breathing has shown efficacy in fibromyalgia (FM), but the mechanisms associated with symptom change are largely unknown. We investigated whether changes in respiratory rate (RR) alone resulted in autonomic changes during normal, paced, and mechanically assisted breathing in untrained FM patients and controls. Participants included 20 FM patients and 14 controls matched for age and body mass index. During a single visit, participants completed three 15-minute breathing sessions: 1) normal breathing, 2) slow-paced breathing, and 3) mechanically assisted breathing (continuous positive airway pressure) while supine. Continuous blood pressure and electrocardiogram were recorded, and measures of heart rate variability (HRV) and spontaneous baroreceptor sensitivity (sBRS) were calculated. During normal breathing, FM patients had higher heart rate (HR), but lower HRV and sBRS variables compared to controls with no difference in RR. Compared to the paced breathing condition, FM patients had significantly lower HR with higher HRV and sBRS variables during mechanically assisted breathing, despite no significant change in RR. Mechanically assisted breathing provided greater benefits in autonomic function than paced breathing in untrained FM patients. Future research will be needed to elucidate the central pathways involved in these autonomic changes and whether training in paced breathing can eventually replicate the results seen in mechanically assisted patients.


Sol-Gel Preparation and Electrorheological Activity of SiO2-TiO2 Composite Powders
The SiO2-TiO2 composite powders with various Si/Ti ratios were prepared by the sol-gel processing, using tetraisopropylorthotitane (Ti(OPri)4) and tetraethoxysilane (Si(OEt)4) as starting materials. The effect of the powder's heat history on the electrorheological (ER) activity of the resulting suspensions, which were prepared by dispersing the powders into silicon oil, was investigated. The infrared spectra, scanning electron microscopy, X-ray diffraction, and zeta potential were used to characterize the structural evolution of the as-prepared gel powders upon heating. The results show a remarkable reduction in gelation time, relative to the single-component systems, due to the combined effects of a higher reactivity of Ti(OPri)4 over Si(OEt)4 and a nucleophilic attack of the Ti atom by the as-hydrolyzed species of Si precursor to form an environment similar to alkali catalysis. It was found that gel powders would gradually eliminate the -OH groups and become denser in structure upon heating, leading to a decrease of ER activity of the resulting suspensions. However, the initial Si/Ti composite compositions have little effect on ER activity behavior. Copyright 1997 Academic Press. Copyright 1997Academic Press


Evaluation of the pressure-redistributing properties of prefabricated foot orthoses in older people after at least 12 months of wear.
Foot problems are highly prevalent in older people. To treat such problems in this age-group prefabricated ('off-the-shelf') foot orthoses are frequently prescribed. However, such devices are susceptible to material compression and deformation, which may reduce their effectiveness over time. Therefore, the aim of this study was to compare the pressure-redistributing properties of new prefabricated orthoses to orthoses worn for at least 12 months. Thirty-one adults (10 males, 21 females) aged over 65 years (mean 75.4, SD 5.2) participated. Plantar pressure data were collected under the rearfoot, midfoot and forefoot using the Pedar(®) in-shoe system while participants walked along an 8m walkway wearing shoes only, new orthoses and old orthoses (orthoses were full length, dual-density prefabricated Formthotic™ devices). Compared to the shoe-only condition, both the new and old orthoses produced significant reductions in peak pressure and maximum force in the rearfoot with corresponding increases in force and contact area in the midfoot. Compared to the new orthoses, the old orthoses exhibited small but significant increases in peak pressure in the rearfoot (6%, p=0.001) and maximum force in the rearfoot (5%, p<0.001) and forefoot (2%, p=0.032). These findings indicate that the prefabricated orthoses evaluated in this study are only slightly less effective at redistributing plantar pressure after at least 12 months of wear.


Recollision dynamics and time delay in strong-field double ionization.
Three-dimensional classical ensembles are employed to study recollision dynamics in double ionization of atoms by 780-nm intense lasers. After recollision one electron typically remains bound to the atom for a portion of a laser cycle, during which time the nucleus strongly influences its direction of motion. The electron then escapes over a suppressed barrier, with its final momentum depending critically on the laser phase at escape. The other electron remains unbound after collision, and typically drifts out in a momentum hemisphere opposite from its motion just after the collision. Several example trajectories at intensity 0.4 PW/cm(2) with various time delays between recollision and ionization are presented.


Proton magnetic resonance spectroscopy in an Italian family with spinocerebellar ataxia type 1.
Linkage and DNA analysis, magnetic resonance (MR) imaging, and single-voxel proton MR spectroscopy were obtained in 10 members of an Italian kindred with spinocerebellar ataxia type 1 (SCA1). The size of the basis pontis, cerebellar hemispheres, middle cerebellar peduncles, and medulla oblongata were decreased in 4 members carrying the SCA1 gene, compared with 6 unaffected subjects. Diffuse signal changes in the pons and cerebellum were observed only in the carrier with the longest disease duration and greatest disability. The N-acetylaspartate/creatine ratio and the choline/creatine ratio in the basis pontis were markedly decreased in 2 symptomatic SCA1 carriers and moderately decreased in 2 asymptomatic SCA1 carriers, compared with the unaffected family members and a control group of 10 healthy volunteers. Minor decreases in the N-acetylaspartate/creatine ratio and the normal choline/creatine ratio were observed in the cerebellar hemisphere of the SCA1 carriers. Reduction of the N-acetylaspartate/creatine ratio, demonstrated by MR spectroscopy in the pons, is likely to reflect a loss of neuronal viability and might represent a biochemical marker of SCA1 more sensitive than brainstem and cerebellum atrophy and signal changes shown by MR imaging.


Critical appraisal of quantitative PCR results in colorectal cancer research: can we rely on published qPCR results?
The use of real-time quantitative polymerase chain reaction (qPCR) in cancer research has become ubiquitous. The relative simplicity of qPCR experiments, which deliver fast and cost-effective results, means that each year an increasing number of papers utilizing this technique are being published. But how reliable are the published results? Since the validity of gene expression data is greatly dependent on appropriate normalisation to compensate for sample-to-sample and run-to-run variation, we have evaluated the adequacy of normalisation procedures in qPCR-based experiments. Consequently, we assessed all colorectal cancer publications that made use of qPCR from 2006 until August 2013 for the number of reference genes used and whether they had been validated. Using even these minimal evaluation criteria, the validity of only three percent (6/179) of the publications can be adequately assessed. We describe common errors, and conclude that the current state of reporting on qPCR in colorectal cancer research is disquieting. Extrapolated to the study of cancer in general, it is clear that the majority of studies using qPCR cannot be reliably assessed and that at best, the results of these studies may or may not be valid and at worst, pervasive incorrect normalisation is resulting in the wholesale publication of incorrect conclusions. This survey demonstrates that the existence of guidelines, such as MIQE, is necessary but not sufficient to address this problem and suggests that the scientific community should examine its responsibility and be aware of the implications of these findings for current and future research.


Independent Clinical Factors Relevant to Prognosis of Patients with Idiopathic Pulmonary Fibrosis.
BACKGROUND The prognosis of idiopathic pulmonary fibrosis (IPF) is the worst among all interstitial lung diseases, and is related to the disease itself. Comorbidities or complications can worsen IPF. We assessed the effect of comorbidities on the survival of IPF patients. A retrospective review of patients with IPF was completed. MATERIAL AND METHODS Information on demographic features, clinical examination, and comorbidities at baseline were obtained. Then, median, 1-year, and 5-year survival was calculated. A total of 380 patients with IPF admitted to Beijing Chao-Yang Hospital from 1 April 2002 to 31 March 2015 were followed up until December 2016. RESULTS Of these 380 patients, 71.9% died during the study period. Median survival was 2.25 years and overall 5-year survival was 28.5%. Also, 86.3% of patients were males. A total of 248 cases underwent lung function tests, and 178 patients underwent bronchoalveolar lavage (BAL). Multivariate analyses showed that forced expiratory volume in 1 second/forced vital capacity (FVC), diffusing capacity of the lungs for carbon monoxide percent predicted, FVC% predicted, the number of macrophages, neutrophils, and lymphocytes in BAL fluid, pulmonary hypertension, hypoxemia, and hydropower disorder were independent prognostic indicators of IPF, GAP gender (G), age (A), and 2 pulmonary physiological parameters (P) model can help to predict prognosis of IPF. CONCLUSIONS Spirometry, GAP model, and BAL are helpful to forecast the prognosis of IPF. IPF patients also suffering from pulmonary arterial hypertension, hypoxemia, and hydropower disorder have a poor prognosis.


Tail shedding in island lizards [Lacertidae, Reptilia]: decline of antipredator defenses in relaxed predation environments.
The ability of an animal to shed its tail is a widespread antipredator strategy among lizards. The degree of expression of this defense is expected to be shaped by prevailing environmental conditions including local predation pressure. We test these hypotheses by comparing several aspects of caudal autotomy in 15 Mediterranean lizard taxa existing across a swath of mainland and island localities that differ in the number and identity of predator species present. Autotomic ease varied substantially among the study populations, in a pattern that is best explained by the presence of vipers. Neither insularity nor the presence of other types of predators explain the observed autotomy rates. Final concentration of accumulated tail muscle lactate and duration of movement of a shed tail, two traits that were previously thought to relate to predation pressure, are in general not shaped by either predator diversity or insularity. Under conditions of relaxed predation selection, an uncoupling of different aspects of caudal autotomy exists, with some elements (ease of autotomy) declining faster than others (duration of movement, lactate concentration). We compared rates of shed tails in the field against rates of laboratory autotomies conducted under standardized conditions and found very high correlation values (r > 0.96). This suggests that field autotomy rates, rather than being a metric of predatory attacks, merely reflect the innate predisposition of a taxon to shed its tail.


Insurance Coverage and Well-Child Visits Improved for Youth Under the Affordable Care Act, but Latino Youth Still Lag Behind.
To examine whether there have been changes in insurance coverage and health care utilization for youth before and after the national implementation of the Patient Protection and Affordable Care Act (ACA) and to assess whether racial and ethnic inequities have improved. Data are from 64,565 youth (ages 0-17 years) participants in the 2011 to 2015 National Health Interview Survey. We conducted multivariate logistic regression analyses to determine how the period after national implementation of the ACA (years 2011-2013 vs years 2014-2015) was associated with health insurance coverage and utilization of health care services (well-child visits, having visited an emergency department, and having visited a physician, all in the past 12 months), and whether changes over the pre- and post-ACA periods varied according to race and Latino ethnicity. The post-ACA period was associated with improvements in insurance coverage and well-child visits for all youth. Latino youth had the largest absolute gain in insurance coverage; however, they continued to have the highest proportion of uninsurance post national ACA implementation. With regard to health care equity, non-Latino black youth were less likely to be uninsured and Latino youth had no significant improvements in insurance coverage relative to non-Latino white youth after national ACA implementation. Inequities in health care utilization for non-Latino black and Latino youth relative to non-Latino white youth did not improve. Insurance coverage and well-child visits have significantly improved for all youth since passage of the ACA, but inequities persist, especially for Latino youth.


QTL and systems genetics analysis of mouse grooming and behavioral responses to novelty in an open field.
The open field is a classic test used to assess exploratory behavior, anxiety and locomotor activity in rodents. Here, we mapped quantitative trait loci (QTLs) underlying behaviors displayed in an open field, using a panel of 53 BXD recombinant inbred mouse strains with deep replication (10 per strain and sex). The use of these strains permits the integration and comparison of data obtained in different laboratories, and also offers the possibility to study trait covariance by exploiting powerful bioinformatics tools and resources. We quantified behavioral traits during 20-min test sessions including (1) percent time spent and distance traveled near the wall (thigmotaxis), (2) leaning against the wall, (3) rearing, (4) jumping, (5) grooming duration, (6) grooming frequency, (7) locomotion and (8) defecation. All traits exhibit moderate heritability making them amenable to genetic analysis. We identified a significant QTL on chromosome M.m. 4 at approximately 104 Mb that modulates grooming duration in both males and females (likelihood ratio statistic values of approximately 18, explaining 25% and 14% of the variance, respectively) and a suggestive QTL modulating locomotion that maps to the same locus. Bioinformatic analysis indicates Disabled 1 (Dab1, a key protein in the reelin signaling pathway) as a particularly strong candidate gene modulating these behaviors. We also found 2 highly suggestive QTLs for a sex by strain interaction for grooming duration on chromosomes 13 and 17. In addition, we identified a pairwise epistatic interaction between loci on chromosomes 12 at 36-37 Mb and 14 at 34-36 Mb that influences rearing frequency in males.


Octamer independent activation of transcription from the kappa immunoglobulin germline promoter.
Previous analyses of immunoglobulin V region promoters has led to the discovery of a common octamer motif which is functionally important in the tissue-specific and developmentally regulated transcriptional activation of immunoglobulin genes. The germline promoters (Ko) located upstream of the J region gene segments of the kappa locus also contain an octamer motif (containing a single base pair mutation and referred to as the variant octamer) which has been shown previously to bind Oct-1 and Oct-2 transcription factors in vitro. To further elucidate the role of this variant octamer motif in the regulation of germline transcription from the unrearranged kappa locus, we have quantitated the relative binding affinity of Oct-1 and Oct-2 for the variant octamer motif and determined the functional role of this octamer motif in transcriptional activation. We find that, although the variant octamer motif binds Oct-1 and Oct-2 in vitro with 5-fold lower affinity than the consensus octamer motif, mutation of the variant octamer motif to either a consensus octamer or non-octamer motif has no effect on transcriptional activation from the germline promoter. We also find significant differences in activation of germline and V region promoters by kappa enhancers. Our results suggest that the germline promoters and V region promoters differ in their dependence on octamer for activation and respond differently to enhancer activation. These findings have important implications in regulation of germline transcription as well as concomitant activation of the V-J recombination of the kappa light chain locus.


[Allergic sensitivity in different groups of patients with atopic dermatitis].
69 patients with atopic dermatitis, aged 16-42 years, were examined. The patients were divided into two groups: group 1 consisted of patients with atopic dermatitis and bronchial asthma and/or allergic rhinitis (25 patients), group 2 consisted of patients without the respiratory syndrome (44 patients). Scarification skin tests made it possible to find out the essential difference in the sensitivity of the examinees in these two groups. In group 1 the prevalence of sensitization to house-dust mites in 23 patients (92%) with monosensitization in 8 patients (32% of the group) was observed. In group 2 sensitivity of house-dust mites was lower: it was registered in 16 patients (36%) with monosensitization in 2 patients (4% of the group). The presence of cross-sensitivity between mite allergens and Candida albicans was established. In accordance with the results of scarification skin tests, treatment included the use of antihistamine preparations, antipruritic remedies and hormonal ointments as well as the elimination of sensitizing allergens. Improvement was registered in 21 patients.


The three-dimensional structure of NeoB: An aminotransferase involved in the biosynthesis of neomycin.
The aminoglycoside antibiotics, discovered as natural products in the 1940s, demonstrate a broad antimicrobial spectrum. Due to their nephrotoxic and ototoxic side effects, however, their widespread clinical usage has typically been limited to the treatment of serious infections. Neomycin B, first isolated from strains of Streptomyces in 1948, is one such drug that was approved for human use by the U.S. Food and Drug Administration in 1964. Only within the last 11 years has the biochemical pathway for its production been elaborated, however. Here we present the three-dimensional architecture of NeoB from Streptomyces fradiae, which is a pyridoxal 5'-phosphate or PLP-dependent aminotransferase that functions on two different substrates in neomycin B biosynthesis. For this investigation, four high resolution X-ray structures of NeoB were determined in various complexed states. The overall fold of NeoB is that typically observed for members of the "aspartate aminotransferase" family with the exception of an additional three-stranded antiparallel β-sheet that forms part of the subunit-subunit interface of the dimer. The manner in which the active site of NeoB accommodates quite different substrates has been defined by this investigation. In addition, during the course of this study, we also determined the structure of the aminotransferase GenB1 to high resolution. GenB1 functions as an aminotransferase in gentamicin biosynthesis. Taken together, the structures of NeoB and GenB1, presented here, provide the first detailed descriptions of aminotransferases that specifically function on aldehyde moieties in aminoglycoside biosynthesis.


Magnetic/NIR-responsive drug carrier, multicolor cell imaging, and enhanced photothermal therapy of gold capped magnetite-fluorescent carbon hybrid nanoparticles.
This paper reports a type of multifunctional hybrid nanoparticle (NP) composed of gold nanocrystals coated on and/or embedded in a magnetite-fluorescent porous carbon core-shell NP template (Fe3O4@PC-CDs-Au) for biomedical applications, including magnetic/NIR-responsive drug release, multicolor cell imaging, and enhanced photothermal therapy. The synthesis of the Fe3O4@PC-CDs-Au NPs firstly involves the preparation of core-shell template NPs with magnetite nanocrystals clustered in the cores and fluorescent carbon dots (CDs) embedded in a porous carbon shell, followed by an in situ reduction of silver ions (Ag(+)) loaded in the porous carbon shell and a subsequent replacement of Ag NPs with Au NPs through a galvanic replacement reaction using HAuCl4 as a precursor. The Fe3O4@PC-CDs-Au NPs can enter the intracellular region and light up mouse melanoma B16F10 cells in multicolor mode. The porous carbon shell, anchored with hydrophilic hydroxyl/carboxyl groups, endows the Fe3O4@PC-CDs-Au NPs with excellent stability in the aqueous phase and a high loading capacity (719 mg g(-1)) for the anti-cancer drug doxorubicin (DOX). The superparamagnetic Fe3O4@PC-CDs-Au NPs with a saturation magnetization of 23.26 emu g(-1) produce localized heat under an alternating magnetic field, which triggers the release of the loaded drug. The combined photothermal effects of the Au nanocrystals and the CDs on/in the carbon shell can not only regulate the release rate of the loaded drug, but also efficiently kill tumor cells under NIR irradiation. Benefitting from their excellent optical properties, their magnetic field and NIR light-responsive drug release capabilities and their enhanced photothermal effect, such nanostructured Fe3O4@PC-CDs-Au hybrid NPs are very promising for simultaneous imaging diagnostics and high efficacy therapy.


Golgi Alpha1,2-Mannosidase IA Promotes Efficient Endoplasmic Reticulum-Associated Degradation of NKCC2.
Mutations in the apically located kidney Na-K-2Cl cotransporter NKCC2 cause type I Bartter syndrome, a life-threatening kidney disorder. We previously showed that transport from the ER represents the limiting phase in NKCC2 journey to the cell surface. Yet very little is known about the ER quality control components specific to NKCC2 and its disease-causing mutants. Here, we report the identification of Golgi alpha1, 2-mannosidase IA (ManIA) as a novel binding partner of the immature form of NKCC2. ManIA interaction with NKCC2 takes place mainly at the cis-Golgi network. ManIA coexpression decreased total NKCC2 protein abundance whereas ManIA knock-down produced the opposite effect. Importantly, ManIA coexpression had a more profound effect on NKCC2 folding mutants. Cycloheximide chase assay showed that in cells overexpressing ManIA, NKCC2 stability and maturation are heavily hampered. Deleting the cytoplasmic region of ManIA attenuated its interaction with NKCC2 and inhibited its effect on the maturation of the cotransporter. ManIA-induced reductions in NKCC2 expression were offset by the proteasome inhibitor MG132. Likewise, kifunensine treatment greatly reduced ManIA effect, strongly suggesting that mannose trimming is involved in the enhanced ERAD of the cotransporter. Moreover, depriving ManIA of its catalytic domain fully abolished its effect on NKCC2. In summary, our data demonstrate the presence of a ManIA-mediated ERAD pathway in renal cells promoting retention and degradation of misfolded NKCC2 proteins. They suggest a model whereby Golgi ManIA contributes to ERAD of NKCC2, by promoting the retention, recycling, and ERAD of misfolded proteins that initially escape protein quality control surveillance within the ER.


Tranexamic acid attenuates inflammatory response in cardiopulmonary bypass surgery through blockade of fibrinolysis: a case control study followed by a randomized double-blind controlled trial.
Extracorporeal circulation induces hemostatic alterations that lead to inflammatory response (IR) and postoperative bleeding. Tranexamic acid (TA) reduces fibrinolysis and blood loss after cardiopulmonary bypass (CPB). However, its effects on IR and vasoplegic shock (VS) are not well known and elucidating these effects was the main objective of this study. A case control study was carried out to determine factors associated with IR after CPB. Patients undergoing elective CPB surgery were randomly assigned to receive 2 g of TA or placebo (0.9% saline) before and after intervention. We performed an intention-to-treat analysis, comparing the incidence of IR and VS. We also analyzed several biological parameters related to inflammation, coagulation, and fibrinolysis systems. We used SPSS version 12.2 for statistical purposes. In the case control study, 165 patients were studied, 20.6% fulfilled IR criteria, and the use of TA proved to be an independent protective variable (odds ratio 0.38, 95% confidence interval 0.18 to 0.81; P < 0.01). The clinical trial was interrupted. Fifty patients were randomly assigned to receive TA (24) or placebo (26). Incidence of IR was 17% in the TA group versus 42% in the placebo group (P = 0.047). In the TA group, we observed a significant reduction in the incidence of VS (P = 0.003), the use of norepinephrine (P = 0.029), and time on mechanical ventilation (P = 0.018). These patients showed significantly lower D-dimer, plasminogen activator inhibitor 1, and creatine-kinase levels and a trend toward lower levels of soluble tumor necrosis factor receptor and interleukin-6 within the first 24 hours after CPB. The use of TA attenuates the development of IR and VS after CPB.


Internal defect scanning of sweetpotatoes using interactance spectroscopy.
While standard visible-light imaging offers a fast and inexpensive means of quality analysis of horticultural products, it is generally limited to measuring superficial (surface) defects. Using light at longer (near-infrared) or shorter (X-ray) wavelengths enables the detection of superficial tissue bruising and density defects, respectively; however, it does not enable the optical absorption and scattering properties of sub-dermal tissue to be quantified. This paper applies visible and near-infrared interactance spectroscopy to detect internal necrosis in sweetpotatoes and develops a Zemax scattering simulation that models the measured optical signatures for both healthy and necrotic tissue. This study demonstrates that interactance spectroscopy can detect the unique near-infrared optical signatures of necrotic tissues in sweetpotatoes down to a depth of approximately 5±0.5 mm. We anticipate that light scattering measurement methods will represent a significant improvement over the current destructive analysis methods used to assay for internal defects in sweetpotatoes.


Phylogeny and Classification of Human Papillomavirus (HPV)16 and HPV18 Variants Based on E6 and L1 genes in Tunisian Women with Cervical Lesions
Background: High-risk human papillomavirus (HPV) types are the main etiological factors for cervical cancer. HPV16 and HPV18 are generally the most common forms associated with development of high-grade cervical lesions. This study was undertaken to identify intratypic variants of HPV16 and HPV18 among women with cervical lesions in Tunisia. Materials and Methods: DNA was extracted from cervical samples collected from 49 women. using a PureLinkTM Genomic DNA mini Kit (Invitrogen). E6 and L1 open reading frames (ORF) were amplified by PCR and viral DNA amplicons were subjected to automated sequencing using Big Dye Terminators technology (Applied Biosystems). The obtained sequences were analyzed using an appropriate software program to allow phylogenetic trees to be generated. Results: HPV16 and HPV18 were detected in 15 and 5 cases, respectively. HPV16 E6 sequences clustered with the European German lineage (A2) whereas one isolate diverged differently in the L1 region and clustered with the African sub-lineage (B1). HPV 18 E6 sequences clustered with the European sub-lineage (A1) but L1 sequences clustered as a new clade which diverged from A1-A5. Conclusions: Our results suggest that the distribution of HPV16 and HPV18 sequences in women with cervical lesions in Tunisia is mainly related to European epidemiological conditions and point to the presence of recombinant HPV forms.


Zika virus non-structural protein NS4A restricts eye growth in Drosophila through regulation of JAK/STAT signaling.
To gain a comprehensive view of the changes in host gene expression underlying Zika virus (ZIKV) pathogenesis, we performed whole-genome RNA sequencing (RNA-seq) of ZIKV-infected Drosophila adult flies. RNA-seq analysis revealed that ZIKV infection alters several and diverse biological processes, including stress, locomotion, lipid metabolism, imaginal disc morphogenesis and regulation of JAK/STAT signaling. To explore the interaction between ZIKV infection and JAK/STAT signaling regulation, we generated genetic constructs overexpressing ZIKV-specific non-structural proteins NS2A, NS2B, NS4A and NS4B. We found that ectopic expression of non-structural proteins in the developing Drosophila eye significantly restricts growth of the larval and adult eye and correlates with considerable repression of the in vivo JAK/STAT reporter, 10XStat92E-GFP At the cellular level, eye growth defects are associated with reduced rate of proliferation without affecting the overall rate of apoptosis. In addition, ZIKV NS4A genetically interacts with the JAK/STAT signaling components; co-expression of NS4A along with the dominant-negative form of domeless or StatRNAi results in aggravated reduction in eye size, while co-expression of NS4A in HopTuml (also known as hopTum ) mutant background partially rescues the hop-induced eye overgrowth phenotype. The function of ZIKV NS4A in regulating growth is maintained in the wing, where ZIKV NS4A overexpression in the pouch domain results in reduced growth linked with diminished expression of Notch targets, Wingless (Wg) and Cut, and the Notch reporter, NRE-GFP Thus, our study provides evidence that ZIKV infection in Drosophila results in restricted growth of the developing eye and wing, wherein eye phenotype is induced through regulation of JAK/STAT signaling, whereas restricted wing growth is induced through regulation of Notch signaling. The interaction of ZIKV non-structural proteins with the conserved host signaling pathways further advance our understanding of ZIKV-induced pathogenesis.This article has an associated First Person interview with the first author of the paper.


Patient, Family, and Physician Satisfaction With Planning for Direct Discharge to Home From Intensive Care Units: Direct From ICU Sent Home Study.
In the new era of decreasing hospital bed availability, there is an increasing rate of direct discharge to home (DDH) from intensive care units (ICUs), despite sparse literature informing this practice. To evaluate patient, family, and ICU attending physician satisfaction with planning for DDH from the ICU and intensivists' current DDH practices and perceptions. Prospective cohort study, using convenience sampling, of adult patients undergoing DDH from an ICU between February 2016 and February 2017 using a modified FS-ICU 24 satisfaction survey completed by patients, family members, and attending physicians at the time of patient discharge to home from the ICU. Seventy-two percent of patients, 37% of family members, and 100% of ICU physicians recruited completed the survey. A majority of patients (89%) and families (78%) were satisfied or very satisfied with DDH. Only 6% of patients and 8% of families were dissatisfied to very dissatisfied with DDH. Conversely, ICU physician satisfaction varied, with only 5% being very comfortable with DDH and the majority (50%) only somewhat comfortable. Twenty percent of staff consultants were uncomfortable to very uncomfortable with the practice of DDH. Thirty-one percent of staff physician respondents felt that patient and family discomfort would be barriers to DDH. Compared to physicians and other allied health professionals, nurses were identified as the most helpful members of the health-care team in preparation for DDH by 98% of patients and 92% of family members. The DDH rates have increased for the past 12 years in our ICUs but declined during the study period (February 2016 to February 2017). Patients and family members are satisfied with the practice of DDH from ICU, although ICU physician satisfaction is more variable. Physician comfort may be improved by data informing which patients may be safely DDH from the ICU.


The impact of services that offer individualised funds, shared management, person-centred relationships, and self-direction on the lived experiences of consumers with mental illness.
Mental health service providers across Australia, including Western Australia (WA), have begun to offer individualised funds, shared management, person-centred and self-directed (SPS) services. No research exists on the impact of SPS services on the lived experiences of these particular consumers. This study explored the impact of a SPS service offered for the first time in WA to consumers with mental illness. Data on sixteen consumers' lived experiences were analysed using an abbreviated grounded theory approach. These data had been developed by the consumers, Guides (staff) and an independent evaluator, and most of it had been collected in the past prior to the commencement of the study. Three over-arching categories, and related subcategories, emerged indicating that 1) access to individualised funds enabled practical and psychological benefits to consumers; 2) consistent contact in shared management and person-centred relationships enhanced the provision of timely and meaningful staff support to consumers; and 3) high quality shared management and person-centred relationships with staff and the opportunity to self-direct enabled consumers' change and growth. SPS services enhanced consumers' lived experiences and enabled staff to provide and consumers to experience timely access to recovery resources, consistent contact, responsive and high quality support, and self-direction of services. In this, consumers changed, grew and achieved desired recovery experiences. The overall impact of the SPS service seemed to be founded on the goodness of fit between person characteristics of staff and consumers, which enabled rich support that provided for corrective emotional experiences. This enabled consumers to build meaningful and hopeful lives where they started to live with, and beyond, their mental illness.


Orchid bee (Hymenoptera: Apidae) community from a gallery forest in the Brazilian Cerrado.
The orchid bees are a very important group of pollinators distributed in the Neotropics. Although a lot of studies concerning male euglossine bees have been done in this region, few works have so far been carried out in the Cerrado biome. This manuscript has the main objective to present the orchid bee community from a Gallery Forest in the Northeastern Brazilian Cerrado landscape, taking account the species composition, abundance, seasonality and hourly distribution. Male euglossine bees were collected monthly from October 2007 to May 2009, in the Reserva Florestal da Itamacaoca belonging to the Companhia de Agua e Esgoto do Maranhão, in Chapadinha municipality, Maranhão State. The scents eucalyptol, eugenol and vanillin were utilized, between 07:00 and 17:00hr, to attract the euglossine males. Cotton balls were dampened with the scents and suspended by a string on tree branches 1.5m above soil level, set 8m from one another. The specimens were captured with entomological nets, killed with ethyl acetate and transported to the laboratory to be identified. A total of 158 individuals and 14 species of bees were recorded. The genus Eulaema was the most representative group of euglossine bees in relation to the total number of the sampled individuals, accounting for 50.6% of bees followed by Euglossa (26.6%), Eufriesea (15.2%) and Exaerete (7.6%). The most frequent species were Eulaema nigrita (27.8%), Eulaema cingulara (19%) and Euglossa cordata (18.3%). Many species typical of forested environments were found in samples, like Euglossa avicula, Euglossa violaceifrons and Eulaema meriana, emphasizing the role played by the Gallery Forests as bridge sites to connect the two great biomes of Amazonia and Atlantic Forest. The occurrence of Exaerete guaykuru represents the second record of this species for the Neotropical region, and both records coming from the Gallery Forest zones. The male euglossine bees were sampled mainly in the dry season, where 62.5% of the individuals were collected in that period. Eufriesea species appeared at the baits only in the wet season. The hourly frequency of bees at scent baits showed a clear preference for the morning period, where 87.9% visited the baits from 07:00 to 12:00hr. The euglossine bee fauna found in the Northeastern Maranhão Cerrado is represented chiefly by species of large geographic distribution and by some forest bee species, where their occurrence is maybe related to to the environmental conditions supported by the Gallery Forest ecosystem.


Epidemiological characterisation of asymptomatic carriers of COVID-19 in Colombia: a cross-sectional study.
Asymptomatic carriers (AC) of the new SARS-CoV-2 represent an important source of spread for COVID-19. Early diagnosis of these cases is a powerful tool to control the pandemic. Our objective was to characterise patients with AC status and identify associated sociodemographic factors. Using a cross-sectional design and the national database of daily occurrence of COVID-19, we characterised both socially and demographically all ACs. Additional correspondence analysis and logistic regression model were performed to identify characteristics associated with AC state (OR, 95% CI). 76.162 ACs (12.1%; 95% CI 12.0% to 12.2%) were identified, mainly before epidemiological week 35. Age≤26 years (1.18; 1.09 to 1.28), male sex (1.51; 1.40 to 1.62), cases imported from Venezuela, Argentina, Brazil, Germany, Puerto Rico, Spain, USA or Mexico (12.6; 3.03 to 52.5) and autochthonous cases (22.6; 5.62 to 91.4) increased the risk of identifying ACs. We also identified groups of departments with moderate (1.23; 1.13 to 1.34) and strong (19.8; 18.6 to 21.0) association with ACs. Sociodemographic characteristics strongly associated with AC were identified, which may explain its epidemiological relevance and usefulness to optimise mass screening strategies and prevent person-to-person transmission.


Identification of artifactual cathepsin D activity in cardiac subcellular fractions related to formation of an iron-EDTA complex.
The conventional assay procedure for cathepsin D (E.C.18.104.22.168) activity in tissue homogenates and subcellular fractions requires incubation with hemoglobin as substrate. Cathepsin D (CD) activity is calculated by determining the increase in absorbance at 280 nm after precipitation of all proteins with trichloroacetic acid. This increase in absorbance (presumably due to the release of tyrosine residues from hemoglobin) is converted to arbitrary CD activity units. Homogenization and fractionation of cardiac tissue frequently requires that ethylenediamine tetraacetic acid (EDTA) be included in the homogenization medium. We have observed that subcellular fractions of cardiac tissue prepared in the presence of EDTA demonstrate residual CD activity despite either quantitative removal of all CD protein by immunoprecipitation or complete inhibition of CD by pepstatin. The present study demonstrates that this 'apparent' CD activity (residual increase in absorbance at 280 nm) is due to the formation of an Fe-EDTA complex which absorbs at 280 nm. Data are presented which demonstrates that the EDTA of the medium complexes with non-heme iron which contaminates commercially available hemoglobin. A method for preparing hemoglobin free of contaminant non-heme iron is described for use in studies of CD metabolism when EDTA is present in the homogenization buffer.


Targeting ErbB3 and Cellular NADPH/NADP+ Abundance Sensitizes Cutaneous Melanomas to Ferroptosis Inducers.
Melanoma is a serious health challenge. Ferroptosis is a regulated form of oxidative cell death that shows varied efficacy in melanoma. We aimed to better understand the molecular basis for this differential ferroptosis sensitivity. We find that elevated expression of ErbB3 (V-Erb-B2 Avian Erythroblastic Leukemia Viral Oncogene Homologue 3) associates with ferroptosis resistance and that ErbB3 knockdown sensitizes to ferroptosis inducers. ErbB3 depletion also promotes a marked reduction in the cellular ratio of GSH/GSSG (reduced/oxidized glutathione) and that of NADPH/NADP+ (reduced/oxidized nicotinamide adenine dinucleotide phosphate), together with an increase in the abundance of the lipid peroxidation product malondialdehyde (MDA). We identify several small molecule inhibitors targeting ErbB3 signaling pathways that also reduce the NADPH/NADP+ and GSH/GSSG ratios, concomitantly sensitizing the melanomas to ferroptosis activators. These findings point to a previously unrecognized role of ErbB3 in ferroptosis sensitivity and provide new insight into pathways that regulate this cell death process.


Drosophila let-7 microRNA is required for remodeling of the neuromusculature during metamorphosis.
The Drosophila let-7-Complex (let-7-C) is a polycistronic locus encoding three ancient microRNAs: let-7, miR-100, and fly lin-4 (miR-125). We find that the let-7-C locus is principally expressed in the pupal and adult neuromusculature. let-7-C knockout flies appear normal externally but display defects in adult behaviors (e.g., flight, motility, and fertility) as well as clear juvenile features in their neuromusculature. We find that the function of let-7-C to ensure the appropriate remodeling of the abdominal neuromusculature during the larval-to-adult transition is carried out predominantly by let-7 alone. This heterochronic role of let-7 is likely just one of the ways in which let-7-C promotes adult behavior.


Binding affinity toward human prion protein of some anti-prion compounds - Assessment based on QSAR modeling, molecular docking and non-parametric ranking.
The present study is based on the quantitative structure-activity relationship (QSAR) analysis of binding affinity toward human prion protein (huPrPC) of quinacrine, pyridine dicarbonitrile, diphenylthiazole and diphenyloxazole analogs applying different linear and non-linear chemometric regression techniques, including univariate linear regression, multiple linear regression, partial least squares regression and artificial neural networks. The QSAR analysis distinguished molecular lipophilicity as an important factor that contributes to the binding affinity. Principal component analysis was used in order to reveal similarities or dissimilarities among the studied compounds. The analysis of in silico absorption, distribution, metabolism, excretion and toxicity (ADMET) parameters was conducted. The ranking of the studied analogs on the basis of their ADMET parameters was done applying the sum of ranking differences, as a relatively new chemometric method. The main aim of the study was to reveal the most important molecular features whose changes lead to the changes in the binding affinities of the studied compounds. Another point of view on the binding affinity of the most promising analogs was established by application of molecular docking analysis. The results of the molecular docking were proven to be in agreement with the experimental outcome.


Perspectives on functional adaptation of the high altitude native.
The major physiological processes that enable humans to attain a complete acclimatization to high altitude are briefly reviewed. The available data indicate that: (a) complete acclimatization to high altitude is associated with changes of environmentally modifiable functional traits such as lung volume but not associated with the expression of genetically controlled features such as chest size; (b) as judged by measurements of maximal aerobic power, the high altitude native has attained at high altitude an adaptation that is comparable to that attained by the low altitude native at sea level; the available information suggests that such adaptation is acquired through growth and development in an hypoxic environment; at present, however, we do not know the developmental modifications that occur within each component of the oxygen transport system, such as ventilation, pulmonary diffusion, and oxygen transport, that enable a sea level native to attain a complete functional adaptation to high altitude; and (c) at comparable altitudes among high altitude natives, there are some inter-regional differences in hemopoietic response, so that the samples derived from mining regions of the Andes are characterized by higher hemoglobin concentration than those derived from non-mining areas or the Himalayas. The source of these differences remains to be investigated.


The role of salivary contents and modern technologies in the remineralization of dental enamel: a narrative review.
Human enamel once formed cannot be biologically repaired or replaced. Saliva has a significant role in remineralization of dental enamel. It not only has a buffering capacity to neutralize the oral cavity's low pH generated after acidic encounters, but also acts as a carrier of essential ions, such as fluoride, calcium and phosphate, which have a positive role in enamel's remineralization. This review discusses how salivary contents, like proteins and enzymes, have a natural role in enamel's mineralization. In addition, the presence of ions, such as fluoride, calcium and phosphate, in saliva further enhances its capability to remineralize the demineralized enamel surface. The review further examines modern innovative technologies, based on biomimetic regeneration systems, including dentin phosphoproteins, aspartate-serine-serine, recombinant porcine amelogenin, leucine-rich amelogenin peptide and nano-hydroxyapatite, that promote enamel remineralization. Fluoride boosters like calcium phosphates, polyphosphates, and certain natural products can also play an important role in enamel remineralization.


Laminar distribution of Fos/calcium-binding protein and Fos/neurofilament protein-labeled neurons in rat motor and sensory cortex after picrotoxin-induced seizures.
Cerebrocortical Fos induction after picrotoxin-induced seizure occurs in spiny neurons and, to a lesser extent, in neurons defined by calcium-binding protein immunoreactivity. In motor and sensory cortex of rats we have defined the laminar distribution of Fos expression in these neurons. Initially we defined the laminar distributions of parvalbumin-, calbindin-D 28K-, and calretinin-immunoreactive aspiny neurons; these were unique for each class and similar across cortical regions. Spiny cells defined by SMI32 immunoreactivity were distributed with two peaks and there were differences between cortical regions. Parvalbumin-immunoreactive neurons exhibited peak numbers where numbers of SMI32-immunoreactive neurons were low. The distribution of Fos induction across laminae matched that of its class for calbindin-D 28K and calretinin neurons; however, Fos induction was less in infragranular compared with supragranular for parvalbumin in motor cortex and SMI32 containing neurons in both cortices. In both these latter cell classes Fos induction was inversely correlated with neuronal size. It is suggested that cell size within some cell classes is one factor that determines the extent of Fos induction within that class following seizures.


The impact of inpatient palliative care on end-of-life care among older trauma patients who die after hospital discharge.
Palliative care (PC) is associated with lower-intensity treatment and better outcomes at the end of life. Trauma surgeons play a critical role in end-of-life (EOL) care; however, the impact of PC on health care utilization at the end of life has yet to be characterized in older trauma patients. This retrospective cohort study using 2006 to 2011 national Medicare claims included trauma patients 65 years or older who died within 180 days after discharge. The exposure of interest was inpatient PC during the trauma admission. A non-PC control group was developed by exact matching for age, comorbidity, admission year, injury severity, length of stay, and post-discharge survival. We used logistic regression to evaluate six EOL care outcomes: discharge to hospice, rehospitalization, skilled nursing facility or long-term acute care hospital admission, death in an institutional setting, and intensive care unit admission or receipt of life-sustaining treatments during a subsequent hospitalization. Of 294,665 patients who died within 180 days after discharge, 2.1% received inpatient PC. Among 5,693 matched pairs, inpatient PC was associated with increased odds of discharge to hospice (odds ratio [OR], 3.80; 95% confidence interval [CI], 3.54-4.09) and reduced odds of rehospitalization (OR, 0.17; 95% CI, 0.15-0.20), skilled nursing facility/long-term acute care hospital admission (OR, 0.43; 95% CI, 0.39-0.47), death in an institutional setting (OR, 0.34; 95% CI, 0.30-0.39), subsequent intensive care unit admission (OR, 0.51; 95% CI, 0.36-0.72), or receiving life-sustaining treatments (OR, 0.56; 95% CI, 0.39-0.80). Inpatient PC is associated with lower-intensity and less burdensome EOL care in the geriatric trauma population. Nonetheless, it remains underused among those who die within 6 months after discharge. Therapeutic/Care management, level III.


Preferential cytolysis of peripheral memory CD4+ T cells by in vitro X4-tropic human immunodeficiency virus type 1 infection before the completion of reverse transcription.
CD4+ T-cell depletion is the hallmark of AIDS pathogenesis. Multiple mechanisms may contribute to the death of productively infected CD4+ T cells and innocent-bystander cells. In this study, we characterize a novel mechanism in which human immunodeficiency virus type 1 (HIV-1) infection preferentially depletes peripheral memory CD4+ T cells before the completion of reverse transcription. Using a recombinant HIV-1 carrying the green fluorescent protein reporter gene, we demonstrate that memory CD4+ T cells were susceptible to infection-induced cell death at a low multiplicity of infection. Infected memory CD4+ T cells underwent rapid necrotic cell death. Killing of host cells was dependent on X4 envelope-mediated viral fusion, but not on virion-associated Vpr or Nef. In contrast to peripheral resting CD4+ T cells, CD4+ T cells stimulated by mitogen or certain cytokines were resistant to HIV-1-induced early cell death. These results demonstrate that early steps in HIV-1 infection have a detrimental effect on certain subsets of CD4+ T cells. The early cell death may serve as a selective disadvantage for X4-tropic HIV-1 in acute infection but may play a role in accelerated disease progression, which is associated with the emergence of X4-tropic HIV-1 in the late stage of AIDS.


Molecular risk stratification of medulloblastoma patients based on immunohistochemical analysis of MYC, LDHB, and CCNB1 expression.
Medulloblastoma is the most common malignant embryonal brain tumor in children. The current clinical risk stratification to select treatment modalities is not optimal because it does not identify the standard-risk patients with resistant disease or the unknown number of high-risk patients who might be overtreated with current protocols. The aim of this study is to improve the risk stratification of medulloblastoma patients by using the expression of multiple prognostic markers in combination with current clinical parameters. Candidate prognostic markers were selected from literature or from medulloblastoma expression data. Selected genes were immunohistochemically analyzed for their prognostic value using medulloblastoma tissue arrays containing 124 well-characterized patient samples. Protein expression analyses showed that the combined expression of three genes was able to predict survival in medulloblastoma patients. Low MYC expression identified medulloblastoma patients with a very good outcome. In contrast, concomitant expression of LDHB and CCNB1 characterized patients with a very poor outcome. Multivariate analyses showed that both expression of MYC and the LDHB/CCNB1 gene signature were strong prognostic markers independent of the clinical parameters metastasis and residual disease. Combined analysis of clinical and molecular markers enabled greater resolution of disease risk than clinical factors alone. A molecular risk stratification model for medulloblastoma patients is proposed based on the signature of MYC, LDHB, and CCNB1 expression. Combined with clinical variables, the model may provide a more accurate basis for targeting therapy in children with this disease.


Digitalisation and COVID-19: The Perfect Storm.
"A ship in the harbour is safe, but that is not what ships are built for," observed that sage 19th century philosopher William Shedd. In other words, technology of high potential is of little value if the potential is not exploited. As the shape of 2020 is increasingly defined by the coronavirus pandemic, digitalisation is like a ship loaded with technology that has a huge capacity for transforming mankind's combat against infectious disease. But it is still moored safely in harbour. Instead of sailing bravely into battle, it remains at the dockside, cowering from the storm beyond the breakwaters. Engineers and fitters constantly fine-tune it, and its officers and deckhands perfect their operating procedures, but that promise is unfulfilled, restrained by the hesitancy and indecision of officialdom. Out there, the seas of the pandemic are turbulent and uncharted, and it is impossible to know in advance everything of the other dangers that may lurk beyond those cloudy horizons. However, the more noble course is for orders to be given to complete the preparations, to cast off and set sail, and to join other vessels crewed by valiant healthcare workers and tireless researchers, already deeply engaged in a rescue mission for the whole of the human race. It is the destiny of digitalisation to navigate those oceans alongside other members of that task force, and the hour of destiny has arrived. This article focuses on the potential enablers and recommendation to maximise learnings during the era of COVID-19.


Leukotrienes in ulcerative colitis: results of a multicenter trial of a leukotriene biosynthesis inhibitor, MK-591.
Leukotrienes (LTs) are believed to be important in the pathogenesis of ulcerative colitis (UC). The aim of this study was to determine whether inhibition of LT biosynthesis with a 5-lipoxygenase inhibitor (MK-591) induces remission in patients with mild to moderate UC. One hundred eighty-three patients with mild to moderately active UC enrolled in this randomized parallel group, double-blind study. Patients received placebo or MK-591 at a dose of 12.5, 50, or 100 mg twice daily for 8 weeks. A subset of patients underwent rectal dialysis to determine LTB4 concentration. MK-591 reduced LTB4 concentrations in rectal dialysate at the final determination. The median percent of baseline LTB4 concentration for 100 mg taken twice daily was 1.4% (n = 4); for 50 mg taken twice daily, 16.5% (n = 6); for 12.5 mg taken twice daily, 12% (n = 6); and for placebo, 78% (n = 6). There was no correlation between reduction of LTB4 and remission. Patients in remission at week 8 were as follows: placebo, 9 of 44 (20.5%); 100 mg taken twice daily, 11 of 43 (25.6%); 50 mg taken twice daily, 8 of 49 (16.3%); and 12.5 mg taken twice daily, 4 of 47 (8.5%) (P > 0.10). MK-591 markedly inhibited LT biosynthesis, but it did not differ significantly from placebo in clinical efficacy. Inhibition of LT biosynthesis was not effective as a single therapeutic modality in active UC.


Endothelin-1 enhances acid-sensing ion channel currents in rat primary sensory neurons.
Endothelin-1 (ET-1), an endogenous vasoactive peptide, has been found to play an important role in peripheral pain signaling. Acid-sensing ion channels (ASICs) are key sensors for extracellular protons and contribute to pain caused by tissue acidosis. It remains unclear whether an interaction exists between ET-1 and ASICs in primary sensory neurons. In this study, we reported that ET-1 enhanced the activity of ASICs in rat dorsal root ganglia (DRG) neurons. In whole-cell voltage-clamp recording, ASIC currents were evoked by brief local application of pH 6.0 external solution in the presence of TRPV1 channel blocker AMG9810. Pre-application with ET-1 (1-100 nM) dose-dependently increased the proton-evoked ASIC currents with an EC50 value of 7.42 ± 0.21 nM. Pre-application with ET-1 (30 nM) shifted the concentration-response curve of proton upwards with a maximal current response increase of 61.11% ± 4.33%. We showed that ET-1 enhanced ASIC currents through endothelin-A receptor (ETAR), but not endothelin-B receptor (ETBR) in both DRG neurons and CHO cells co-expressing ASIC3 and ETAR. ET-1 enhancement was inhibited by blockade of G-protein or protein kinase C signaling. In current-clamp recording, pre-application with ET-1 (30 nM) significantly increased acid-evoked firing in rat DRG neurons. Finally, we showed that pharmacological blockade of ASICs by amiloride or APETx2 significantly alleviated ET-1-induced flinching and mechanical hyperalgesia in rats. These results suggest that ET-1 sensitizes ASICs in primary sensory neurons via ETAR and PKC signaling pathway, which may contribute to peripheral ET-1-induced nociceptive behavior in rats.


Genomic Instability Decreases in HIV Patient by Complementary Therapy with Rosmarinus officinalis Extracts.
Genomic instability is associated with increased oxidative stress in patients with human immunodeficiency virus (HIV). The aim of this study was to determine the effect of intake of methanolic and aqueous extracts of Rosmarinus officinalis on genomic instability in HIV patients. We studied 67 HIV patients under pharmacological treatment with ATRIPLA who were divided into three groups: group 1, patients under ATRIPLA antiretroviral therapy; group 2, patients with ATRIPLA and rosemary aqueous extract (4 g/L per day); and group 3, patients with ATRIPLA and rosemary methanolic extract (400 mg/day). The genomic instability was evaluated through the buccal micronucleus cytome assay. Oral epithelial cells were taken at the beginning and 1 and 4 months later. The groups that received the pharmacological therapy with ATRIPLA and the complementary therapy with R. officinalis extracts showed a decrease in the number of cells with micronuclei and nuclear abnormalities compared with the group that only received ATRIPLA. The complementary therapy with R. officinalis decreased the genomic instability in HIV patients.


Measuring surface dynamics of biomolecules by total internal reflection fluorescence with photobleaching recovery or correlation spectroscopy.
The theoretical basis of a new technique for measuring equilibrium adsorption/desorption kinetics and surface diffusion of fluorescent-labeled solute molecules at solid surfaces has been developed. The technique combines total internal reflection fluorescence (TIR) with either fluorescence photobleaching recovery (FPR) or fluorescence correlation spectroscopy (FCS). A laser beam totally internally reflects at a solid/liquid interface; the shallow evanescent field in the liquid excites the fluorescence of surface adsorbed molecules. In TIR/FPR, adsorbed molecules are bleaching by a flash of the focused laser beam; subsequent fluorescence recovery is monitored as bleached molecules exchange with unbleached ones from the solution or surrounding nonilluminated regions of the surface. In TIR/FCS, spontaneous fluorescence fluctuations due to individual molecules entering and leaving a well-defined portion of the evanescent field are autocorrelated. Under appropriate experimental conditions, the rate constants and surface diffusion coefficient can be readily obtained from the TIR/FPR and TIR/FCS curves. In general, the shape of the theoretical TIR/FPR and TIR/FCS curves depends in a complex manner upon the bulk and surface diffusion coefficients, the size of the iluminated or observed region, and the adsorption/desorption/kinetic rate constants. The theory can be applied both to specific binding between immobilized receptors and soluble ligands, and to nonspecific adsorption processes. A discussion of experimental considerations and the application of this technique to the adsorption of serum proteins on quartz may be found in the accompanying paper (Burghardt and Axelrod. 1981. Biophys. J. 33:455).


[Features of spatial organization of EEG and psychophysiological characteristics of the person with the divergent and convergent types of thinking].
The psychophysiological indicators of spatial synchronization of biopotential at different types of mental processes in humans: non verbal-divergent, nonverbal-convergent, verbal-divergent and verbal-convergent were analyzed. The unequal relationship between the productivity of the implementation of tests on these types of thinking was revealed. The closest significant correlation exists between the productivity of the verbal-divergent and verbal-convergent thinking, and the lowest--between the productivity of nonverbally-divergent and nonverbally-convergent thinking. The differences in the topographical maps of the spatial synchronization of biopotential at different types of thinking was marked. They are most pronounced in the implementation of two non-verbal tasks, minimal--in two verbal tasks. Differences between different types of thinking are also manifested in the degree of coherence gain biopotential of the performance tests in comparison with the background (open eyes). Some physiological properties of the person that contribute to the divergent (creative) tests have a negative impact on the implementation of converged (tedious) tests. The findings are discussed in terms of differences in the level of general activation and participation of different ways of processing information (simultaneous and successiveness).


The future is now! A supplemental webinar series to the First International Pediatric Cardio-Oncology Meeting.
Planning for the First International Pediatric Cardio-Oncology Meeting has been underway since early 2019, with the original date in October 2020 delayed due to the COVID-19 pandemic. But patients continue to need care, research carries on, and the ability to learn from our colleagues remains one of the most important tools in our collective ability to advance the field. Through collaboration with Heart University (www.heartuniversity.org), a free web-based global education resource and training tool with an emphasis on acquired and congenital heart disease, we are able to provide colleagues around the world with focused sessions similar to those that will be expanded at the in-person meeting. The first such two-hour webinar was presented live online on December 16, 2020, and moving forward similar webinars will be offered approximately every other month for the next year leading up to the in-person meeting in 2022, with all sessions available online afterward for on-demand viewing. Although we are excited to get together with our colleagues in person, why wait until then to share what we know? The future is now!


Fentanyl preloading for rapid-sequence induction of anesthesia.
Protecting the patient's airway is of paramount importance in the induction of general anesthesia. For the patient at risk of regurgitation of stomach contents, the rapid-sequence (crash) induction provides protection, but at the expense of increased stress response to laryngoscopy and intubation. This stress response is especially dangerous for the patient at risk for myocardial ischemia. The purpose of this study was to examine the efficacy of using low-dose fentanyl (5 micrograms/kg) to reduce cardiovascular and neuroendocrine stress responses to rapid-sequence induction. Thirty patients were randomly assigned to a rapid-sequence induction protocol either with or without fentanyl preloading. Fentanyl-preloaded patients (fentanyl group) received 2 mg/kg of thiopental whereas patients who were not preloaded with fentanyl (control group) received 4 mg/kg of thiopental. Data collected as indices of the stress response included heart rate, systolic, diastolic, and mean blood pressures, and plasma concentrations of catecholamines (epinephrine, norepinephrine, dopamine) and beta-endorphin. Electrocardiograms (modified V5 lead) were monitored for dysrhythmias and ST segment depression. Control patients had higher systolic, diastolic, and mean blood pressures after intubation than did patients given fentanyl (P less than 0.05). Although the incidence of dysrhythmias was decreased by fentanyl (20% vs 42%), this difference was not statistically significant. Plasma concentrations of beta-endorphin and norepinephrine increased significantly in control patients but not in patients given fentanyl (P less than 0.05). Low-dose fentanyl (5 micrograms/kg) reduces some aspects of the stress response to rapid-sequence induction of anesthesia.


Effect of MicroRNA-210 on the Growth of Ovarian Cancer Cells and the Efficacy of Radiotherapy.
The objective of this study is to explore the role of miR-210 in the growth of ovarian cancer cells and the correlation with radiotherapy and to elucidate underlying molecular mechanisms. Human ovarian cancer cell lines OVCAR3 and SKOV3 were cultured in vitro, and miR-210 over-expression and low-expression ovarian cancer cell models were established by cell transfection. MTT assay was used to detect the proliferation activity. Transwell was used to detect the migration and invasion abilities. Western blot measured the expression of proteins related to cell proliferation, migration, and invasion. The cells were treated with different doses of ionizing radiation, and then the cell proliferation activity was detected by MTT. The expression of apoptosis-related proteins was detected by Western blot. The Caspase-Glo® Kit was used to detect the activity of cellular caspase 3/7 enzymes. The proliferation, migration, and invasion abilities of miR-210 over-expression ovarian cancer cells were increased (p < 0.05), the expressions of PTEN and E-cadherin were decreased, and the expression of p-Protein kinase B (AKT), N-cadherin, Snail, and Vimentin were elevated. After ionizing radiation, the sensitivity of miR-210 over-expression cells to radiotherapy was decreased, the expression of apoptosis-related protein Bax was decreased, the expression of Bcl-2 was increased, and the activity of cellular caspase 3/7 enzyme was reduced (p < 0.05). miR-210 can promote the proliferation, migration, and invasion of ovarian cancer cells by activating the AKT signaling pathway and regulating the expression of Epithelial-mesenchymal transition-related proteins. miR-210 can reduce the sensitivity of ovarian cancer cells to radiotherapy by inhibiting apoptosis, which might serve as a potential target for the treatment of ovarian tumors.


Smokeless and combustible tobacco use among 148,944 South Asian adults: a cross-sectional study of South Asia Biobank.
Tobacco use, in both smoking and smokeless forms, is highly prevalent among South Asian adults. The aims of the study were twofold: (1) describe patterns of SLT and combustible tobacco product use in four South Asian countries stratified by country and sex, and (2) assess the relationships between SLT and smoking intensity, smoking quit attempts, and smoking cessation among South Asian men. Data were obtained from South Asia Biobank Study, collected between 2018 and 2022 from 148,944 men and women aged 18 years and above, living in Bangladesh, India, Pakistan, or Sri Lanka. Mixed effects multivariable logistic and linear regression were used to quantify the associations of SLT use with quit attempt, cessation, and intensity. Among the four South Asian countries, Bangladesh has the highest rates of current smoking (39.9% for male, 0.4% for female) and current SLT use (24.7% for male and 23.4% for female). Among male adults, ever SLT use was associated with a higher odds of smoking cessation in Bangladesh (OR, 2.88; 95% CI, 2.65, 3.13), India (OR, 2.02; 95% CI, 1.63, 2.50), and Sri Lanka (OR, 1.36; 95% CI, 1.14, 1.62). Ever SLT use and current SLT use was associated with lower smoking intensity in all countries. In this large population-based study of South Asian adults, rates of smoking and SLT use vary widely by country and gender. Men who use SLT products are more likely to abstain from smoking compared with those who do not.


Diffusion in kappa-carrageenan gel beads.
Using a well-mixed and temperature-led vessel, the diffusion characteristics of various solutes into spherical kappa-carrageenan gel beads were experimentally investigated. The diffusion coefficient of glucose was markedly affected by the glucose concentration and the operating temperature. In all cases the diffusivity obtained was noticeably smaller than that of glucose in pure water. The experimental data also indicated an inverse relationship between the diffusivity and the polymer concentration used in the gel preparation. As well, the glucose diffusivity was affected by the presence of other solutes in the glucose solution. Electrolytes such as ammonium sulfate, KCl, and CaCl(2) were observed to enhance the diffusion coefficient. On the other hand, the addition of arginine or bovine serum albumin had an adverse effect on the diffusivity. No diffusion of albumin into the gel beads was observed, and such a solute created a significant mass transfer resistance during the diffusion process.


Consensus-based good practice guidelines for clinical psychologists to support care staff in enabling sexual expression in people with intellectual disabilities-A Delphi study.
Care staff supporting people with intellectual disabilities (PWID) report accepting views on PWID's sexual expression, but people with intellectual disabilities report their sexual expression is restricted by care staff. We recruited a panel of 17 UK clinical psychologists experienced in helping care staff support PWID's sexual expression. We used the Delphi Method to develop consensus-based practice guidelines for UK clinical psychologists supporting care staff in this way. Having proposed three guidelines each in Round One, panel members reached consensus (≥90% agreement) that 12 were important, falling under four themes: "Addressing staff attitudes," "Addressing uncertainty about rights and responsibilities of people with intellectual disabilities," "Locating the problem, being part of the solution," and "Supporting care staff to understand and reflect upon their role." Clinical psychologists help care staff support PWID's sexual expression by normalizing care staff concerns, encouraging reflection, clarifying PWID's rights, and prompting those at managerial and service level to support care staff.


Pancreatitis and alcoholism disorder the renal tubule and impair reclamation of some low molecular weight proteins.
We sought to determine whether the clinical setting in which pancreatitis occurs affects the incidence and distribution of increased values of renal clearance of amylase relative to creatinine, CAm/CCr, and whether the increased values reflect a tubular disorder that impairs renal reclamation of certain low molecular weight proteins. We measured the renal clearance of three low molecular weight proteins (amylase, beta 2-microglobulin, and lysozyme) and urinary excretion of three lysosomal enzymes that originate from the renal tubule in three groups of patients (alcoholic pancreatitis, pancreatitis without alcoholism, and alcoholism without pancreatitis). When compared to normal controls, the mean CAm/CCr was significantly elevated in alcoholic pancreatitis (p less than 0.05) but not in equally severe pancreatitis without alcoholism nor in alcoholism without pancreatitis. The clearance ratio of beta 2-microglobulin was significantly increased in each of the three patient groups; mean clearance ratio of lysozyme was not significantly increased in any of the patient groups. Excretion of each of the three lysosomal enzymes was significantly increased in each of the patient groups. We conclude that the etiology of pancreatitis affects the distribution of values for CAm/CCr, impaired tubular reclamation of amylase is the mechanism of the increase in CAm/CCr, and a factor or factors associated with both pancreatitis and with alcoholism per se appear to disorder the renal tubule and to impair tubular reclamation of some but not all low molecular weight proteins-a novel finding of considerable potential significance.


The crystal structure of ORF-9b, a lipid binding protein from the SARS coronavirus.
To achieve the greatest output from their limited genomes, viruses frequently make use of alternative open reading frames, in which translation is initiated from a start codon within an existing gene and, being out of frame, gives rise to a distinct protein product. These alternative protein products are, as yet, poorly characterized structurally. Here we report the crystal structure of ORF-9b, an alternative open reading frame within the nucleocapsid (N) gene from the SARS coronavirus. The protein has a novel fold, a dimeric tent-like beta structure with an amphipathic surface, and a central hydrophobic cavity that binds lipid molecules. This cavity is likely to be involved in membrane attachment and, in mammalian cells, ORF-9b associates with intracellular vesicles, consistent with a role in the assembly of the virion. Analysis of ORF-9b and other overlapping genes suggests that they provide snapshots of the early evolution of novel protein folds.


A chitosan-hyaluronan-based hydrogel-hydrocolloid supports in vitro culture and differentiation of human mesenchymal stem/stromal cells.
Three-dimensional (3D) cell culture platforms are increasingly utilized due to their ability to more closely mimic the in vivo microenvironment compared to traditional two-dimensional methods. Limitations of currently available 3D materials include lack of cell attachment, long polymerization times, and inclusion of undefined xenobiotics, and cytotoxic cross-linkers. Evaluated here is a unique hydrogel comprised of polyelectrolytic complex (PEC) fibers formed by hyaluronic acid and chitosan (CT). When hydrated with fetal bovine serum containing human mesenchymal stem/stromal cells (hMSCs), a hydrogel with an elastic modulus of 264±38 Pa formed in seconds with cells distributed throughout the matrix. Scanning electron microscopy showed a lattice-like meshwork of PEC fibers forming irregular compartments. hMSCs showed 48% viability during the first 24 h, with cell populations thereafter reaching a steady state for 14 days. hMSCs in the matrix were induced to differentiate to chondrogenic, osteogenic, and adipogenic phenotypes. Emergent features, at days 56 and 70, consisted of chondrogenesis on the surface of hydrogels induced to osteogenic and adipogenic phenotypes. Results indicate that this matrix may be useful for tissue engineering and disease modeling applications.


Effect of Gastric Fluid Volume on the In Vitro Dissolution and In Vivo Absorption of BCS Class II Drugs: a Case Study with Nifedipine.
Nifedipine is a BCS Class II drug used for treatment of hypertension and preterm labor. Large inter-patient variability in nifedipine absorption results in variable exposure among different patients. We conducted in vitro dissolution studies to compare nifedipine dissolution from immediate release (IR) capsules with different volumes of dissolution media. Results from dissolution studies were used to design a crossover study in healthy volunteers to evaluate the effect of coadministered water volume with nifedipine 10 mg IR capsules on nifedipine pharmacokinetics, especially absorption (C max, t max, and AUC0-6). Dissolution studies demonstrated that larger gastric fluid volumes result in enhanced nifedipine dissolution from 10 mg IR cosolvent capsules (73 vs. 17% in 200 and 100 mL simulated gastric fluid, respectively, at 30 min). The pharmacokinetic crossover study in healthy volunteers (N = 6) did not show a significant effect of the water volume administered with the capsule (50 vs. 250 mL) on C max, t max, or AUC0-6 of orally administered nifedipine IR capsules (10 mg). However, administration of large water volumes resulted in lower variability in nifedipine C max (47 vs. 70% for 250 and 50 mL, respectively). Administration of large water volumes with nifedipine 10 mg IR cosolvent capsules may reduce inter-individual variability in plasma exposure. Evaluation of similar effects in other BCS Class II drugs is recommended.


Glenohumeral internal rotation deficit in table tennis players.
Table tennis requires rapid and extreme movements that may result in shoulder adaptations, such as glenohumeral internal rotation deficit, which is a risk factor for several injuries. This study compared range of motion of internal and external rotation and total rotation motion of glenohumeral joint between dominant and non-dominant shoulders of table tennis players. This is a cross-sectional observational study. Twenty healthy male table tennis players that were enrolled in an official table tennis league took part in this study (mean age: 22.9 ± 12.9 years, time of sports practice: 6.2 ± 7.12 years). Measurements of passive glenohumeral external rotation and internal rotation were taken with the individuals in the supine and sidelying positions. Total rotation motion was calculated by summing external and internal rotations. The dominant side showed decreased internal rotation when compared to non-dominant side in both supine (mean difference: 14.9°, p = 0.02) and sidelying positions (mean difference: 16.3°, p = 0.01). No significant difference (p > 0.05) was found for external rotation and total rotation motion between dominant and non-dominant shoulders. The findings indicate that table tennis players exhibit glenohumeral internal rotation deficit of dominant shoulder.


Total prostate specific antigen stability confirmed after long-term storage of serum at -80C.
We characterized the long-term stability of total prostate specific antigen in serum samples after storage at -80C from 2001 until 2007. From the San Antonio Biomarkers of Risk biorepository we chose serum samples from white men 55.2 to 80.5 years old (median age 63.3) in which prostate specific antigen was measured in 2001. These men were not diagnosed with prostate cancer by 2007. A blocked randomization scheme was used to randomly select 47 serum samples with prostate specific antigen values spread over the reference ranges 0.0 to 0.4 (10), 0.5 to 0.9 (10), 1.0 to 1.9 (10), 2.0 to 3.9 (11) and 4.0 to 10.0 ng/ml (6) for repeat measurement by the same assay in 2007. Spearman's correlation coefficient was used to calculate the correlation and the paired t test was used to test the null hypothesis of no average difference between prostate specific antigen measured in 2001 and 2007. Median prostate specific antigen values were 1.20 ng/ml (range 0.20 to 7.20) in 2001 and 1.30 (range 0.20 to 6.70) in 2007. In 2001 and 2007 mean +/- SD prostate specific antigen was 1.76 +/- 1.59 and 1.84 +/- 1.64 ng/ml, and the coefficient of variation was 0.91 and 0.89, respectively. The correlation between prostate specific antigen values in 2001 and 2007 was high (0.995). Prostate specific antigen values in 2007 were consistently and statistically significantly higher than in 2001 (mean 0.08 ng/ml, p = 0.005). Systematic and random error increased slightly with increasing prostate specific antigen. Agreement between total prostate specific antigen values measured from serum samples in 2001, stored at -80C for 7 years and then remeasured was highly correlative.


[The efficacy and safety of pitavastatin].
In short-term, phase III or IV studies in Asian and European patients, pitavastatin 1, 2 and 4 mg once daily reduced LDL-Cholesterol (LDL-C) 34%, 42% and 47%, respectively. Pitavastatin provided sustained LDL-C-lowering efficacy over up to 60 weeks' therapy in extension studies. In comparative studies pitavastatin 4 mg and simvastatin 40 mg reduced LDL-C similarly, reduction in triglycerides and increase in HDL-Cholesterol (HDL-C) was more prominent with pitavastatin. In comparative studies with atorvastatin, pitavastatin 4mg was found to be more effective than 20 mg of atorvastatin, and a little less effective than 40 mg of atorvastatin. The increase in HDL-C demonstrated in short term studies sustained in long term, whereas with atorvastatin the increase in HDL-C was less prominent. Pitavastatin was generally well tolerated in these studies and most treatment emergent adverse events were mild or moderate and their frequency was not different from other statins. Pitavastatin did not appear to adversely affect glucose metabolism parameters (e.g. fasting blood glucose, fasting plasma insulin, glycated hemoglobin) in short- and longer-term prospective and post-marketing surveillance studies in adults. In conclusion, pitavastatin is an effective treatment option in adults with primary hypercholesterolemia and combined (mixed) dyslipidemia, including those at risk of developing type 2 diabetes.


[The meconium antigen exhibiting oncofetal properties].
A rabbit antiserum to the meconium antigen of the human fetal intestine is obtained by immunization of rabbits by this substance preparation. The preparation is extracted from meconium by the sulphate ammonium (70% saturation) treatment and gel filtration of supernatant with selection of the 240 kD fractions. In the indirect immunoperoxidase reaction the antiserum reacts with epithelium of certain normal and fetal tissues. It displays oncofetal features in colon, since it reacts with fetal and malignant epithelium and does not react with normal epithelium of this organ. The developed test-system may be used in pathomorphology for the morphological and functional state of colon mucosa evaluation.


Association between medication adherence and quality of life of patients with diabetes and hypertension attending primary care clinics: a cross-sectional survey.
To evaluate the association between medication adherence and quality of life (QoL) of patients with diabetes and/or hypertension attending primary care clinics. In this cross-sectional study, patients with at least one long-term condition (hypertension or diabetes mellitus) meeting the eligibility criteria were recruited from five primary care clinics in Saudi Arabia. Arabic version of Morisky Medication Adherence Scale (MMAS-8) and the World Health Organization Quality of Life-BREF (WHOQOL-BREF) tool were used to assess medication adherence and QoL, respectively. Patients' sociodemographic, medical and medication data were collected using a structured, pilot-tested data collection form. Three hundred patients with a mean (± SD) age of 56.79 (12.8) years participated in the study. Fifty-eight had hypertension only, 96 had diabetes (Type 1 or 2), and 146 had both hypertension and diabetes. After adjusting for socioeconomic characteristics, multiple linear regression analysis found that adherent patients had significantly higher mean overall perception of QoL and health scores by 14.6 (P = 0.001) and 17.2 (P = 0.001) points, respectively, compared to non-adherent patients. In addition, irrespective of the type of long-term condition, adherence status was found to be an independent predictor of all QoL domains. There is an association between medication adherence and QoL among patients with diabetes and/or hypertension attending primary care clinics. Medication adherence should be assessed and emphasised during routine clinical consultations in primary care in order to achieve the desired clinical outcomes and overall well-being of patients.


Translation attenuation by PERK balances ER glycoprotein synthesis with lipid-linked oligosaccharide flux.
Endoplasmic reticulum (ER) homeostasis requires transfer and subsequent processing of the glycan Glc(3)Man(9)GlcNAc(2) (G(3)M(9)Gn(2)) from the lipid-linked oligosaccharide (LLO) glucose(3)mannose(9)N-acetylglucosamine(2)-P-P-dolichol (G(3)M(9)Gn(2)-P-P-Dol) to asparaginyl residues of nascent glycoprotein precursor polypeptides. However, it is unclear how the ER is protected against dysfunction from abnormal accumulation of LLO intermediates and aberrant N-glycosylation, as occurs in certain metabolic diseases. In metazoans phosphorylation of eukaryotic initiation factor 2alpha (eIF2alpha) on Ser(51) by PERK (PKR-like ER kinase), which is activated by ER stress, attenuates translation initiation. We use brief glucose deprivation to simulate LLO biosynthesis disorders, and show that attenuation of polypeptide synthesis by PERK promotes extension of LLO intermediates to G(3)M(9)Gn(2)-P-P-Dol under these substrate-limiting conditions, as well as counteract abnormal N-glycosylation. This simple mechanism requires eIF2alpha Ser(51) phosphorylation by PERK, and is mimicked by agents that stimulate cytoplasmic stress-responsive Ser(51) kinase activity. Thus, by sensing ER stress from defective glycosylation, PERK can restore ER homeostasis by balancing polypeptide synthesis with flux through the LLO pathway.


Interactive visualization and analysis of hierarchical neural projections for data mining.
Dimensionality reducing mappings, often also denoted as multidimensional scaling, are the basis for multivariate data projection and visual analysis in data mining. Topology and distance preserving mapping techniques--e.g., Kohonen's self-organizing feature map (SOM) or Sammon's nonlinear mapping (NLM)--are available to achieve multivariate data projections for the following interactive visual analysis process. For large data bases, however, NLM computation becomes intractable. Also, if additional data points or data sets are to be included in the projection, a complete recomputation of the mapping is required. In general, a neural network could learn the mapping and serve for arbitrary additional data projection. However, the computational costs would also be high, and convergence is not easily achieved. In this work, a convenient hierarchical neural projection approach is introduced, where first an unsupervised neural network--e.g., an SOM--quantizes the data base, followed by fast NLM mapping of the quantized data. In the second stage of the hierarchy, an enhancement of the NLM by a recall algorithm is applied. The training and application of a second neural network, which is learning the mapping by function approximation, is quantitatively compared with this new approach. Efficient interactive visualization and analysis techniques, exploiting the achieved hierarchical neural projection for data mining, are presented.


[Clinical and genetic analysis of a patient with tyrosinemia type I but without elevated succinylacetone].
To analyze the clinical manifestation and genetic mutation of a child with tyrosinemia type I but without elevated succinylacetone. Clinical data of the patient was collected. Tandem mass spectrometry and gas chromatography mass spectrometry were used to analyze the blood amino acid and urine organic acid component of the proband. DNA was extracted from the child and his parents and used for mutation analysis. The proband was of acute type, with features including hepatomegaly, jaundice, anemia and tendency of bleeding. Serum levels of Tyrosine, Methionine and Phenylalanine were 397.12 μmol/L, 896.16 μmol/L and 292.52 μmol/L, respectively, which all distinctly exceeded the normal levels. The level of phenyllactic acid and 4-hydroxyphenyl-lactic acid of proband's urine were 17.4 μmol/L and 417.0 μmol/L, respectively, which also exceeded the normal levels, but the level of succinylacetone was within the normal range. Compound heterozygous mutations of the FAH gene, namely c.634delT (p.L212Wfs*20) and c.455G>A (p.W152X), were detected in the proband, which were both predicted to be pathogenic and were inherited from her father and mother, respectively. For children with tyrosinemia type I, detection of urine succinylacetone by gas phase mass spectrometry can be negative. The diagnosis of tyrosinemia type I must rely on genetic testing and/or enzymatic assaying.


A discrete-scatterer model for ultrasonic images of rough surfaces.
Automated analysis of ultrasonic images could be greatly improved with model-based Bayesian methods for image analysis. Such an approach would require an accurate probabilistic image model representing ultrasonic images in terms of the gross shape of underlying anatomical structure. Existing probabilistic models for ultrasonic image data do not adequately incorporate structure shape or system characteristics; thus, a substantially new approach is warranted. Toward that goal, we have developed models for the imaging system and rough surface with the following objectives: (1) accuracy in representation of basic image characteristics such as the texture and intensity, (2) a minimum of computational requirements, and (3) a form that is naturally extendable to an appropriate probabilistic image model. The imaging system was modeled as a linear system with a separable three-dimensional point-spread function with an envelope of Gaussian curves in each dimension. The rough surface was modeled as a collection of discrete scatterers placed on the continuum and parametrized by a surface roughness and scatterer concentration. Models were evaluated by a visual comparison of actual and simulated images of a cadaveric lumbar vertebra. The gross shape of the vertebral surface was estimated from computed tomography images of the vertebra, and simulated images were generated using the models and the gross surface shape. Actual images were registered with the surface and simulated images to within 2 mm. The similarity of the actual and simulated images was quite remarkable considering the simplicity of the models. Differences between the images were less than those between two simulated images separated by 0.4 mm or one-fifth the registration error. Further assessment of the models would require a statistical approach not yet available. The models do, however, provide the basis for the development of a computationally tractable probabilistic image model for image analysis. Such a model will provide the means for a statistical evaluation of the system and surface models.


Mesenchymal chondroprogenitor cell origin and therapeutic potential.
Mesenchymal progenitor cells, a multipotent adult stem cell population, have the ability to differentiate into cells of connective tissue lineages, including fat, cartilage, bone and muscle, and therefore generate a great deal of interest for their potential use in regenerative medicine. During development, endochondral bone is formed from a template of cartilage that transforms into bone; however, mature articular cartilage remains in the articulating joints, where its principal role is reducing friction and dispersing mechanical load. Articular cartilage is prone to damage from sports injuries or ageing, which regularly progresses to more serious joint disorders, such as osteoarthritis. Osteoarthritis is a degenerative joint disease characterized by the thinning and eventual wearing of articular cartilage, and affects millions of people worldwide. Due to low chondrocyte motility and proliferative rates, and complicated by the absence of blood vessels, cartilage has a limited ability to self-repair. Current pharmaceutical and surgical interventions fail to generate repair tissue with the mechanical and cellular properties of native host cartilage. The long-term success of cartilage repair will therefore depend on regenerative methodologies resulting in the restoration of articular cartilage that closely duplicates the native tissue. For cell-based therapies, the optimal cell source must be readily accessible with easily isolated, abundant cells capable of collagen type II and sulfated proteoglycan production in appropriate proportions. Although a cell source with these therapeutic properties remains elusive, mesenchymal chondroprogenitors retain their expansion capacity with the promise of reproducing the structural or biomechanical properties of healthy articular cartilage. As current knowledge regarding chondroprogenitors is relatively limited, this review will focus on their origin and therapeutic application.


Root traits and δ13C and δ18O of durum wheat under different water regimes.
Plant growth, root characteristics and the stable carbon (δ13C) and oxygen (δ18O) composition were studied in durum wheat. Four recombinant inbred lines with good agronomic adaptation were grown under well watered (WW) and water stress (WS) conditions until mid-grain filling in lysimeters. Gas exchange was measured in the flag leaf just before harvest and then the aerial dry matter (Aerial DM), root weight density (RWD) and root length density (RLD) and the specific root length (SRL) were evaluated and the δ13C and δ18O of the roots, the flag leaf blade and the spike were analysed. Water stress decreased stomatal conductance, plant accumulated transpiration and Aerial DM, whereas δ13C and δ18O increased. Genotypic differences were found for all gas-exchange and root traits and isotope signatures. Aerial DM was positively correlated with RLD, regardless of the water regime, whereas it was negatively correlated with δ13C and δ18O, but only under WW conditions. Moreover, RWD and RLD were negatively related to both δ13C and δ18O under the WW regime, but no clear pattern existed under WS. Our study supports the use of δ13C and δ18O as proxies for selecting root traits associated with higher growth in the absence of water stress.


Quantitative phase contrast imaging with a nonlocal angle-selective metasurface.
Phase contrast microscopy has played a central role in the development of modern biology, geology, and nanotechnology. It can visualize the structure of translucent objects that remains hidden in regular optical microscopes. The optical layout of a phase contrast microscope is based on a 4 f image processing setup and has essentially remained unchanged since its invention by Zernike in the early 1930s. Here, we propose a conceptually new approach to phase contrast imaging that harnesses the non-local optical response of a guided-mode-resonator metasurface. We highlight its benefits and demonstrate the imaging of various phase objects, including biological cells, polymeric nanostructures, and transparent metasurfaces. Our results showcase that the addition of this non-local metasurface to a conventional microscope enables quantitative phase contrast imaging with a 0.02π phase accuracy. At a high level, this work adds to the growing body of research aimed at the use of metasurfaces for analog optical computing.